dbSNP rs181860403: RHCE:p.Leu60Ile (chr1-25408840-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020485.8(RHCE):c.178C>A(p.Leu60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000896 in 1,283,276 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000094 ( 34 hom. )

Consequence

RHCE
NM_020485.8 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.694

Publications

5 publications found

Variant links:

Genes affected

RHCE (HGNC:10008): (Rh blood group CcEe antigens) The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene which encodes both the RhC and RhE antigens on a single polypeptide and a second gene which encodes the RhD protein. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. A mutation in this gene results in amorph-type Rh-null disease. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Aug 2016]

RHCE Gene-Disease associations (from GenCC):

Rh deficiency syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RHCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15248543).

BS2

High Homozygotes in GnomAdExome4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHCE	NM_020485.8 link	c.178C>A	p.Leu60Ile	missense_variant	Exon 2 of 10	ENST00000294413.13	NP_065231.4	P18577A0A220QMN8A0A1L3H056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHCE	ENST00000294413.13 link	c.178C>A	p.Leu60Ile	missense_variant	Exon 2 of 10	1	NM_020485.8	ENSP00000294413.6		P18577

Frequencies

GnomAD3 genomes

AF:

0.0000489

AC:

AN:

122618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000413

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000264

AC:

AN:

189058

AF XY:

0.0000198

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000436

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000939

AC:

109

AN:

1160658

Hom.:

Cov.:

AF XY:

0.0000874

AC XY:

AN XY:

572146

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000607

AC:

AN:

32930

American (AMR)

AF:

0.00

AC:

AN:

32030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19278

East Asian (EAS)

AF:

0.00

AC:

AN:

21444

South Asian (SAS)

AF:

0.00

AC:

AN:

51350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.000110

AC:

100

AN:

909082

Other (OTH)

AF:

0.000148

AC:

AN:

47170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000489

AC:

AN:

122618

Hom.:

Cov.:

AF XY:

0.0000341

AC XY:

AN XY:

58694

show subpopulations

African (AFR)

AF:

0.000126

AC:

AN:

39644

American (AMR)

AF:

0.00

AC:

AN:

11278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2542

East Asian (EAS)

AF:

0.000413

AC:

AN:

2420

South Asian (SAS)

AF:

0.00

AC:

AN:

2340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53890

Other (OTH)

AF:

0.00

AC:

AN:

1642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000632

AC:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.69

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.93

N;N;N;N;N;N

REVEL

Benign

0.057

Sift

Benign

0.44

T;T;T;T;T;T

Sift4G

Benign

0.65

T;T;T;T;T;T

Polyphen

0.69, 0.48, 0.055

.;P;.;P;B;.

Vest4

0.46

MVP

0.043

MPC

0.35

ClinPred

0.046

GERP RS

0.34

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over